Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene is known to have toxic effects on the blood and bone marrow, but its impact at levels below the U.S. occupational standard of 1 part per million (ppm) remains uncertain. In a study of 250 workers exposed to benzene, white blood cell and platelet counts were significantly lower than in 140 controls, even for exposure below 1 ppm in air. Progenitor cell colony formation significantly declined with increasing benzene exposure and was more sensitive to the effects of benzene than was the number of mature blood cells. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, influenced susceptibility to benzene hematotoxicity. Thus, hematotoxicity from exposure to benzene occurred at air levels of 1 ppm or less and may be particularly evident among genetically susceptible subpopulations.
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PMID:Hematotoxicity in workers exposed to low levels of benzene. 1670 67

This paper reviews the literature on the influence of metabolic and DNA repair polymorphisms of biological indicators of genotoxic risk commonly used in biomonitoring occupational exposure to carcinogens. Genetic polymorphisms which influence biomarkers (urinary metabolites, protein and DNA adducts), include P450 cytochromes (CYPs) and glutathione S-transferases (GSTs) in exposure to polycyclic aromatic hydrocarbons (PAHs), and acetyltransferases (NATs) in exposure to aromatic amines (AAs). As regards exposure to benzene, also relevant is the influence of epoxydohydrolase (EPHX) and NAD(P)H quinone oxidoreductase (NQO1) on the urinary excretion of t,t-muconic and phenylmercapturic acids. With respect to occupational exposure to styrene, EPHX significantly influences the levels of Chromosome Aberrations (CAs), strongly predictive genotoxic biomarkers of cancer risk. Some recent studies examine the role of polymorphisms linked to DNA repair genes in the modulation of genotoxic risk associated with PAH exposure, both for life-style (dietary and smoking behaviour) and for occupational reasons. In addition, molecular epidemiology studies (case/control studies) of lung cancer in smokers published since 2000 may also be viewed as representing models of effects due to exposure to carcinogenic mixtures, some of which are present in the working environment (e.g., BaP, benzene, AAs). Almost all studies show the clearcut influence (i.e., increased lung cancer risk with OR > or = 2) of genetic polymorphisms linked to PAH metabolism (in particular, CYPIA1, GSTM1 and P1). Among the risk factors are the different mutagen sensitivity towards, for instance, bleomycin and BaP (tested in vitro), the reduced repair capacity to DNA damage induced by BaP, and increases in some biomarkers of early biological effect (DNA adducts and stable CAs). Other risk factors, such as heredity (siblings of cancer patients have a risk factor > or = 3 with respect to the general population), ethnicity (Chileans > Caucasians; Japanese > Americans) and gender (women > men), have still not been clearly characterized and these are also reported in this paper. It is clear from the above that genetic differences underlie individual susceptibility to lung cancer, whether caused by exposure to tobacco smoke or to occupational carcinogens like PAHs. Some of these indicators of exposure/individual susceptibility can be evaluated in groups at high risk of occupational lung cancer, such as coke-oven and aluminium workers and those exposed to coal tar fumes and soot, etc., with the aim of identifying subjects who are susceptible due to the high concentrations of carcinogens found in their working environment.
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PMID:[Individual susceptibility to occupational carcinogens: the evidence from biomonitoring and molecular epidemiology studies]. 1558 38

Air pollution, containing high-level of ultrafine particles (UFP) and benzene, is a prominent environmental health problem in many cities of the World. We investigated the level of oxidative DNA damage in mononuclear blood cells (MNBC) by the comet assay as DNA strand breaks (SB) and formamidopyrimidine DNA glycosylase (FPG) sensitive sites in residents from three urban locations in Cotonou, Benin (taxi-moto drivers, subjects living near roads with intense traffic and suburban residents) and rural residents. Exposure was characterized by urinary excretion of S-phenylmercapturic acid (S-PMA), a biomarker of benzene exposure, and by ambient UFP. There were clear stepwise gradients with respect to ambient UFP, S-PMA excretion and oxidative DNA damage with rural subjects < suburban subjects < residents living near highly trafficed roads<taxi-moto drivers. Polymorphisms in glutathione peroxidase (GPX), NAD(P)H:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) genes were assessed for effect modification. Subjects with GSTT1 null genotype had lower urinary S-PMA excretion than subjects carrying the plus genotype. Urinary S-PMA excretion correlated with SB (R = 0.17) and FPG sites (R = 0.25) in MNBC. The correlation between S-PMA and SB was strongest in subjects with NQO1*1/*2 and *2/*2 genotypes (R = 0.37), and between S-PMA and FPG sensitive sites in subjects with the GSTP1*B/*B genotype (R = 0.39). In conclusion, this study shows that urban air with high levels of benzene and UFP is associated with elevated levels of SB and FPG sites in MNBC, and that NQO1 and GST genes may modulate the effect.
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PMID:Ultrafine particulate matter and high-level benzene urban air pollution in relation to oxidative DNA damage. 1559 Oct 89

This report is part of an extensive biomarker study conducted in a Chinese occupational population with benzene exposures ranging from 0.06 to 122 ppm (median exposure of 3.2 ppm). All urinary benzene metabolites measured in this study were significantly elevated after exposure to benzene at or above 5 ppm. Among these metabolites, however, only S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) showed a significant exposure-response trend over the exposure range from 0 to 1 ppm (for S-PMA, p<0.0001 and for t,t-MA, p=0.006). For benzene exposure monitoring, both S-PMA and t,t-MA were judged to be good and sensitive markers, which detected benzene exposure at around 0.1 and 1 ppm, respectively. Polymorphisms of the metabolic genes, including CYP2E1, quinone oxidoreductase (NQO1), GSTT1, and myeloperoxidase (MPO), were identified and did not show significant effects on the formation of metabolites, except GSTT1 on S-PMA. The production rate of S-PMA from benzene in exposed workers with GSTT1 null alleles (24.72+/-32.48 microg/g creatinine/ppm benzene) was significantly lower than that in subjects with the wild type of GSTT1 (59.84+/-47.66 microg/g creatinine/ppm benzene, p<0.0001). Further regression analysis of S-PMA production rate on GSTT1 genotype with adjustment of sex, age, benzene exposure, and cotinine levels indicated that the genotype of GSTT1 plays a critical role in determining the inter-individual variations of S-PMA formation from benzene exposure. Therefore, the individual genotype of GSTT1 needs to be identified and considered while using S-PMA as a marker to estimate the personal exposure levels of benzene in future population studies.
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PMID:Biomarkers of benzene: urinary metabolites in relation to individual genotype and personal exposure. 1593 3

Quinone oxidoreductases (NQO1 and NQO2) are cytosolic proteins that catalyze metabolic reduction of quinones and its derivatives to protect cells against redox cycling and oxidative stress. In humans, a high percentage of individuals with myeloid and other types of leukemia are homo- and heterozygous for a null mutant allele of NQO1. The NQO2 locus is also highly polymorphic in humans. Recently, we generated NQO1-/- and NQO2-/- mice deficient in NQO1 and NQO2 protein and activity, respectively. These mice showed no detectable developmental abnormalities and were indistinguishable from wild type mice. Interestingly, all the mice lacking expression of NQO1 and NQO2 protein demonstrated myelogenous hyperplasia of the bone marrow and increased granulocytes in the peripheral blood. Decreased apoptosis contributed to myelogenous hyperplasia. The studies on short-term exposure of NQO1-/- mice to benzene demonstrated substantially greater benzene-induced toxicity, as compared to wild type mice.
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PMID:Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity. 3283 29

Benzene induces bone marrow cytotoxicity and chromosomal breaks as a primary mode of action for the induction of bone marrow toxicity. Our research group has used genetically modified mouse models to examine metabolic and genomic response pathways involved in benzene induced cytotoxicity and genotoxicity in bone marrow and in hematopoietic stem cells (HSC). We review our studies using NQO1-/- mice and mEH-/- mice to examine the roles of these enzymes, NAD(P)H:quinone oxidoreductase-1 (NQO1) and microsomal epoxide hydrolase (mEH) in mediating benzene-induced toxicity. NQO1 catalyzes the detoxication of benzene quinone metabolites and mEH catalyzes the hydrolysis of benzene oxide. Our studies using gene expression profiling of bone marrow and enriched HSC populations isolated from the bone marrow of benzene-exposed mice demonstrate differential gene expression responses of key genes induced by inhaled benzene. These studies show that benzene toxicity is regulated by a number of genetic pathways that affect the production of reactive metabolites and DNA damage response pathways in a target tissue.
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PMID:Use of genetically modified mouse models to assess pathways of benzene-induced bone marrow cytotoxicity and genotoxicity. 1593 12

Biomarkers of benzene exposure and effect were evaluated in 158 Bulgarian petrochemical workers and 50 matched controls. Air exposures to benzene averaged about 1.8 ppm, for workers and 0.02 ppm for controls. Urinary trans,trans-muconic acid, and S-phenylmuconic acid, showed dose response relationships with benzene air exposure. The dose response curve for DNA single strand breaks (SSB), but not for the metabolites, showed a saturation effect. NQO1 genotype had a significant effect on SSB. We conclude that the pathways for these metabolites may be distinct from those involved in some forms of genotoxic damage induced by benzene.
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PMID:Biomarkers of exposure and effect in Bulgarian petrochemical workers exposed to benzene. 1593 22

The NAD(P)H:quinone acceptor oxidoreductase (NQO) gene family belongs to the flavoprotein clan and, in the human genome, consists of two genes (NQO1 and NQO2). These two genes encode cytosolic flavoenzymes that catalyse the beneficial two-electron reduction of quinones to hydroquinones. This reaction prevents the unwanted one-electron reduction of quinones by other quinone reductases; one-electron reduction results in the formation of reactive oxygen species, generated by redox cycling of semiquinones in the presence of molecular oxygen. Both the mammalian NQO1 and NQO2 genes are upregulated as a part of the oxidative stress response and are inexplicably overexpressed in particular types of tumours. A non-synonymous mutation in the NQO1 gene, leading to absence of enzyme activity, has been associated with an increased risk of myeloid leukaemia and other types of blood dyscrasia in workers exposed to benzene. NQO2 has a melatonin-binding site, which may explain the anti-oxidant role of melatonin. An ancient NQO3 subfamily exists in eubacteria and the authors suggest that there should be additional divisions of the NQO family to include the NQO4 subfamily in fungi and NQO5 subfamily in archaebacteria. Interestingly, no NQO genes could be identified in the worm, fly, sea squirt or plants; because these taxa carry quinone reductases capable of one- and two-electron reductions, there has been either convergent evolution or redundancy to account for the appearance of these enzyme functions whenever they have been needed during evolution.
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PMID:Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. 1659 77

We have previously shown that deficiency in the biotransformation enzyme glutathione-S-transferase theta (GSTT1) is a risk factor for multiple myeloma (MM). The present case-control study of 102 MM patients and 205 controls revealed a significant trend in increasing risk of MM with inheritance of multiple putative 'high risk' genetic variants in related pathways of benzene detoxification. Individuals who carried polymorphisms for GSTT1 null and/or high activity microsomal epoxide hydrolase (mEH 113YY+139HR or 113YY+139RR or 113YH+139RR) and/or low activity NAD(P)H:quinone oxidoreductase 1 (NQO1 187PS/SS) were 1.65, 2.49 and 13 times more likely to have MM (P(trend)=0.001).
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PMID:Genetic variations in benzene metabolism and susceptibility to multiple myeloma. 1915 49

Twenty-seven selenium compounds and sixteen structurally related organosulfur compounds were tested for quinone reductase (QR) and glutathione-S-transferase (GST) inducing activity in murine hepatoma (Hepa 1c1c7) cells. Sixteen selenium compounds were able to double QR activity, and seven of them also doubled GST activity. The nine most potent compounds, dimethyl diselenide, 2,5-diphenyl- selenophene, dibenzyl diselenide, methylseleninic acid, diphenyl diselenide, benzeneseleninic acid, benzene selenol, triphenylselenonium chloride, and ebselen (2-phenyl- 1,2-benzisoselenazol-3(2H)-one), doubled QR-specific activity at levels lower than 7 microM. The concentration-dependence of QR induction and cell growth inhibition were linearly correlated (P < 0.001, r2 = 0.96) among the group of organoselenium compounds with putative selenol-generating potential, implying that both responses of Hepa 1c1c7 cells were based on these selenol metabolites.
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PMID:Induction of phase II enzyme activity by various selenium compounds. 1704 77


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